Hearing Biomarkers in Alzheimer's Disease

阿尔茨海默病的听力生物标志物

• 批准号: 10740266
• 负责人: Hong-Bo Zhao
• 金额: $ 81.83万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-15 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10740266
• 关键词: APP-PS1; Acceleration; Acoustic Stimulation; Acoustics; Alzheimer disease detection; Alzheimer' s Disease; Alzheimer' s disease diagnosis; Alzheimer' s disease pathology; Alzheimer' s disease patient; Alzheimer' s disease related dementia; Alzheimer' s disease risk; Alzheimer’s disease biomarker; Amyloid; Area; Auditory; Auditory Evoked Potentials; Auditory system; Behavioral; Biological Markers; Brain; CBA/CaJ Mouse; Cell Nucleus; Cognitive; Conflict (Psychology); Dementia; Detection; Development; Diagnosis; Early Diagnosis; Electrophysiology (science); Genetic; Genomics; Goals; Hearing; Hearing problem; Human; Human Amyloid Precursor Protein; Impaired cognition; Link; Measures; Memory; Memory Loss; Motor; Mus; Mutation; Nerve Degeneration; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurons; Outcome Measure; Pathologic; Persons; Photic Stimulation; Presbycusis; Prevalence; Prevention; Role; Sensory; Startle Reaction; Symptoms; System; TREM2 gene; Techniques; Testing; Therapeutic Effect; Therapeutic Intervention; Time; aged; auditory pathway; behavior test; cost; dementia risk; early detection biomarkers; epidemiology study; familial Alzheimer disease; functional decline; hearing impairment; high risk; improved; mouse model; mutant; neural; normal aging; preventive intervention; protein aggregation; protein expression; screening; sensory system; spiral ganglion; tau Proteins; transcriptome sequencing

Summary Alzheimer's disease (AD) is a common neurodegenerative disease with progressive memory loss and cognitive decline. Early detection is critical for prevention and treatment of AD and AD related dementia (ADRD). It has been estimated that delay of the onset of dementia by even one year would reduce the prevalence of dementia by 10%. Recently, increasing evidence demonstrates that AD pathological changes can occur in sensory associated brain areas 5-10 years early before typical AD symptoms present, suggesting that they could serve as early biomarkers for AD/ADRD detection and diagnosis. Hearing is an important neural sense. Hearing loss also is a major high-risk factor for dementia. Recent studies demonstrated that visual and auditory stimulations with gamma oscillation cycles could reduce amyloid-ȕ (Aȕ expression in the brain and improve memory in AD mice. We hypothesize that hearing has a critical role in AD development and progression. However, hearing is an understudied field in AD study. Little is known about AD-induced hearing changes. Previous epidemiological studies demonstrated that AD patients could have hearing loss. However, since aged persons usually have age-related hearing loss (ARHL), it was hard to distinguish AD-induced hearing decline from ARHL in those epidemiological studies. The link to AD pathology also could not be determined and remained unclear. In this project, we will use AD mouse models to identify and characterize AD-induced functional and pathological changes in the auditory system (Aim 1). Both familial AD (fAD) and sporadic AD (sAD) mouse models will be used to increase experimental rigor. AD-induced functional changes in the auditory system will be longitudinally examined and assessed during AD development and progression. These changes will be linked to Aȕ and Tau protein expressions and genomic changes in the auditory system, which will be assessed by RNA sequencing. The AD hearing marker, thus, can be unambiguously determined. In Aim 2, we will use both AD and ARHL mouse models to further distinguish AD-induced hearing decline from ARHL. We will also define the impact of hearing loss on AD/ADRD development and progression and test whether ARHL can accelerate/exacerbate AD/ADRD development and progression. These proposed studies can improve our understanding AD pathology and the role of hearing in AD/ADRD development and progression. Such information is also critical and required for understanding the underlying mechanism for the therapeutic effect of acoustic stimulation against AD and further improving treatment and prevention.

总结 阿尔茨海默病（AD）是一种常见的神经退行性疾病， 认知能力下降早期发现是预防和治疗AD及AD相关痴呆的关键 （ADRD）.据估计，即使延迟痴呆症发作一年， 痴呆症患病率下降10%。近年来，越来越多的证据表明，AD的病理改变 在典型的AD症状出现之前5-10年， 提示它们可作为AD/ADRD检测和诊断的早期生物标志物。听力是重要的 神经感觉听力损失也是痴呆症的主要高危因素。最近的研究表明， 视觉和听觉刺激与γ振荡周期可以减少淀粉样蛋白-β（AAP 12表达在 改善AD小鼠的记忆力。我们假设听力在AD的发展中起着关键作用， 进展然而，在AD研究中，听觉是一个未被充分研究的领域。关于AD引起的听力知之甚少 变化以往的流行病学研究表明，AD患者可能有听力损失。然而，在这方面， 由于老年人常伴有年龄相关性听力损失（ARHL）， 在这些流行病学研究中，与AD病理学的联系也不可能是 确定和仍然不清楚。在这个项目中，我们将使用AD小鼠模型来识别和表征 AD诱导的听觉系统功能和病理变化（目的1）。家族性AD（fAD）和 将使用散发性AD（sAD）小鼠模型来增加实验的严谨性。AD引起的功能变化 将在AD发展和进展期间纵向检查和评估听觉系统中的听觉系统。 这些变化将与听觉系统中的Akt和Tau蛋白表达和基因组变化有关， 这将通过RNA测序来评估。因此，AD听力标记可以被明确地确定。 在目标2中，我们将使用AD和ARHL小鼠模型来进一步区分AD诱导的听力下降和 阿尔。我们还将定义听力损失对AD/ADRD发展和进展的影响，并测试 ARHL是否会加速/加重AD/ADRD的发展和进展。这些研究建议 可以提高我们对AD病理学和听力在AD/ADRD发展中的作用的理解， 进展这些信息对于理解这些疾病的潜在机制也是至关重要的， 声刺激对AD的治疗效果，并进一步改善治疗和预防。